Ovarian cancer is the leading cause of death of gynecological cancers. Our hypothesis is that the integration of paracrine, endocrine and microenvironmental cues affecting the tumor vasculature can explain the rise in aggresiveness of ovarian cancer in post-menopausal women and that those key regulatory elements, once identified, could serve for improving efficacy of therapy. Our long term objective is to reveal the regulatory mechanisms that control angiogenesis during disease progression. Over the last 5 years our work led to a number of insights on progression of ovarian cancer: 1) Kinetic MRI studies of vascularization and growth of dormant ovarian tumors revealed that the critical switch for initiation of tumor progression was not the establishment of blood vessels, but rather their subsequent stabilization, which correlated with infiltration of host-derived myofibroblasts. 2) Tumor cells and myofibroblasts express different angiogenic growth factors affecting vascular plasticity and stability respectively, thus leading to large vascular phenotypic heterogeneity, that was detectable by intergrating MRI data of vascular permeability and maturation and correlating the distribution of multimodality MR/optical contrast material with gene expression. 3) An important obstacle for progression of avascular ovarian micrometastases is antiangiogenic hyaluronan, a gel-like material, secreted by the mesotheslial cells, the target for ovarian cancer metastasis. We found that elevated gonadotropins as found at menopause, can induce tumor-cell expression of CD44, the hyaluronan receptor. To overcome the antiangiogenic effect of hyaluronan, ovarian cancer cells release hyaluronidase, thus converting hyaluronan into pro-angiogenic fragments. Our specific aims for the coming 5 years are: Aim 1) to analyze the mechanisms by which myofibroblasts are recruited to tumors and induce tumor progression and how they can be utilized for delivery of therapeutic material to the tumor vasculature; for that aim we developed a novel approach for labeling and tracking of myofibroblasts by MRI. Aim 2) to determine the role of hyaluronan synthesis, binding and degradation in progression of ovarian cancer; to facilitate that, a new smart MRI contrast material was developed which is activated by hyaluronidase; and Aim 3) to determine the impact of menopause and the crosstalk between changes in the microenvironment, growth factor expression and hormones in regulating progression and metastasis in ovarian cancer. [unreadable] [unreadable] [unreadable]